Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review

Jardim, Denis Leonardo Fontes; Groves, Eric; Breitfeld, Philip P.; Kurzrock, Razelle

doi:10.1016/j.ctrv.2016.10.009

Cited by 88 publications

(65 citation statements)

References 64 publications

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“…2 Therefore, it is important to consider whether it is ethical to conduct large phase 3 RCTs of new cancer drugs despite evidence of lack of efficacy in phase 2. Although some previous studies have shown that negative Phase 3 trials are being conducted without Phase 2, 3,4 we found that Phase 3 RCTs were also conducted despite a preceding negative Phase 2. Previous studies have also shown that the response rates of drugs fall in Phase 3 versus Phase 2 trials, hence the chances for success of a drug that has already failed a Phase 2 is low.…”

contrasting

confidence: 81%

Negative phase 3 randomized controlled trials: Why cancer drugs fail the last barrier?

Gyawali

Addeo

2018

Intl Journal of Cancer

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contrasting

confidence: 81%

Negative phase 3 randomized controlled trials: Why cancer drugs fail the last barrier?

Gyawali

Addeo

2018

Intl Journal of Cancer

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“…Despite high investments to develop new cancer therapeutics, about 90% of drugs finally tested in clinical trials fail 34, 35 . Spheroids with sizes of 250–750 µm are detectable in cancer patients and, correspondingly, traditional testing methods are increasingly being complemented by 3D models of human tumors.…”

Section: Discussionmentioning

confidence: 99%

Small cell lung cancer: model of circulating tumor cell tumorospheres in chemoresistance

Klameth

Rath

Hochmaier

et al. 2017

Sci Rep

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Small cell lung cancer (SCLC) represents 15% of lung cancers and is characterized by early dissemination, development of chemoresistance and a poor prognosis. A host of diverse drugs failed invariably and its mechanisms of global chemoresistance have not been characterized so far. SCLC represents the prototype of an aggressive and highly metastatic tumor which is ultimately refractory to any treatment. High numbers of circulating tumor cells (CTCs) allowed us to establish 5 CTC cell lines (BHGc7, 10, 16, 26 and UHGc5) from patients with recurrent SCLC. These cell lines exhibit the typical SCLC markers and CTCs of all patients developed spontaneously large multicellular aggregates, termed tumorospheres. Ki67 and carbonic anhydrase 9 (CAIX) staining of tumorosphere sections revealed quiescent and hypoxic cells, respectively. Accordingly, comparison of the chemosensitivity of CTC single cell suspensions with tumorospheres demonstrated increased resistance of the clusters against chemotherapeutics commonly used for treatment of SCLC. Therefore, global chemoresistance of relapsing SCLC seems to rely on formation of large tumorospheres which reveal limited accessibility, lower growth fraction and hypoxic conditions. Since similar tumor spheroids were found in other tumor types, SCLC seems to represent a unique tumor model to study the association of CTCs, metastasis and drug resistance.

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“…92 Although a great deal of useful data is available to position therapeutics in likely responder subpopulations, many clinical trials are still not designed to optimise patient enrolment on the basis of a preclinically validated biomarkers. 93 …”

Section: Drug Discovery Development and Deliverymentioning

confidence: 99%

Future cancer research priorities in the USA: a Lancet Oncology Commission

Jaffee

Dang

Agus

et al. 2017

The Lancet Oncology

171

129

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We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

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Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review

Cited by 88 publications

References 64 publications

Negative phase 3 randomized controlled trials: Why cancer drugs fail the last barrier?

Negative phase 3 randomized controlled trials: Why cancer drugs fail the last barrier?

Small cell lung cancer: model of circulating tumor cell tumorospheres in chemoresistance

Future cancer research priorities in the USA: a Lancet Oncology Commission

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